Surg Endosc (1990) 4: 150-153

Surgical Endoscopy © Springer-Verlag 1990

Photodynamic therapy of esophageal carcinoma Tetsuya Okunaka 1, 2, Harubumi Kato 1, Chimori Conaka 1, Hideki Yamamoto 1, Anthony Bonaminio 2, and Mark L. Eckhauser 2 1Department of Surgery, Tokyo Medical College, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160 Japan 2 Department of Surgery, MetroHealth Medical Center, Case Western Reserve University, 3395 Scranton Road, Cleveland, OH 44109, USA

Summary. Photodynamic therapy (PDT) utilizing either hematoporphyrin derivative or Photofrin II is proving to be an effective modality in the treatment of early superficial (ES) or advanced invasive (AI) carcinoma of the esophagus. An argon-pumped dye laser was used to deliver 630 nm light via quartz fibers passed through the b i o p s y channel of a gastroscope after intravenous injection of photosensitizer. Between 1982 and 1989, 20 patients (ES = 6; AI = 14} were treated in this manner. Complete remission was obtained in 4 of 6 ES cases, and the mean survival after PDT alone or in combination with other therapy was 27 months. Five patients remain alive to date. In the AI group, significant remissions were obtained in 6 cases while partial remissions were observed in another 8. The mean dysphagia grade improved from 4.0 to 2.8. We conclude that PDT is efficacious in the treatment of ES esophageal cancer, where complete remission may be achieved, and as palliative therapy in advanced cases to alleviate dysphagia.

malignant tissue [10]. The effectiveness of PDT in the treatment of malignant tumors by Dougherty et al. [4] has initiated increasing attention to this new therapeutic modality. A wide variety of malignancies have been treated by this method, and according to Dougherty's review of the world literature, over 3000 patients have been treated thus far with PDT [3]. Clinical PDT at the Tokyo Medical College began in 1980 [5]. Since then, 310 of our patients have been treated with PDT, including 157 patients with lung and 18 with esophageal cancer. In spite of vigorous efforts by physicians, the prognosis in esophageal cancer remains quite poor. Regardless of whether surgical procedures (including resection, bypass, dilation and prosthetic insertion), chemotherapy or radiation therapy is used, less than 5% survive 5-years [13]. In this paper, we describe and evaluate our experience utilizing PDT in the treatment of both early-stage superficial and advanced invasive forms of esophageal cancer.

Key words: Photodynamic therapy - Hematoporphyrin derivative - Argon dye laser - Esophageal cancer Endoscope

Patients and methods Selection o f p a t i e n t s

The clinical efficacy of photodynamic therapy (PDT) is based on the selective localization of hematoporphyrin derivative (HpD) in malignant tissue. Photoirradiation by red light of 630 nm wavelength initiates a photochemical reaction which is ultimately lethal to cells. In this manner, selective necrosis of tumor tissue can be achieved. It has been known for nearly a century that a photochemical reaction occurs when photosensitizing compounds are exposed to light [14]. In 1961, HpD was prepared from hematoporphyrin hydrochloride by treatment with acetic acid and was shown to have a great affinity for

Offprint requests to: T. Okunaka

Twenty patients (17 male and 3 female) with esophageal cancer were treated with PDT between 1982 and 1989. The mean age was 70 years with a range of 50 to 84 years. Patients were categorized as having early-stage superficial lesions if tumor involvement was limited to the mucosa and submucosa only after endoscopic evaluation and biopsy, endosonography and CT scanning. All other patients by definition were categorized as having advanced invasive lesions. Histologically, all

tumors were squamous cell carcinomas. Patients were made fully aware of the experimentalnature of this clinical trial and informed consent was obtained from all patients treated in this study.


Patients received either 3.0 mg HpD (Photofrin I; Photofrin Medical, Cheektowaga, N. Y.) per kilogram body weight intravenouslyor 2.0 mg Photofrin II (PhotofrinMedical) per kilogram, which is a purified derivative of Photofrin I. PDT was performed with topical anesthesia and



~ I ArgonL.... '

"~ I




, i .... • H7 -- Sinil,:pCD)wg22injected ~ / ~ I I 48-72hbeforePDT


~ retainedby......

Fig. 1. Schematic representation of photodynamic therapy

intravenous sedation 4 8 - 7 2 h after injection of the photosensitizer, An argon dye laser system (Cooper Medical 770) delivered 630 nm monochromatic light through a 400-gin transmission quartz fiber inserted through the instrument channel of a fiberoptic gastroscope. The power output was adjusted to 9 0 - 8 0 0 mW at the fiber tip, and the lesions were photoirradiated either with a straight-tip fiber placed 1 - 3 cm from superficially invading lesions or with a cylindrical diffusing fiber for partially obstructing lesions (Fig. 1). The laser fiber was inserted directly into the tumor in patients with lesions totally obstructing the esophageal lumen. With respect to superficial lesions, the light dose delivered was measured in joules/cm 2 of tissue irradiated, calculated from variables which included time of exposure, fiber-tip power output, and surface area of the exposed tumor. Alternatively, when the fiber tip

Table 1. Dysphagia grade (from [9]) Grade Description Able to swallow all solids without difficulty Difficulty swallowing some hard solids but able to swallow semisolids (blenderized or pureed foods) Unable to swallow any solids; able to swallow liquids without difficulty Difficulty in swallowing liquids Unable to swallow anything, including saliva

was inserted directly into a tumor (interstitial PDT), the total joules delivered was approximated. The tumor response to PDT was evaluated by endoscopy, cytology, and histology 1 month after treatment in patients that did not undergo surgical resection following PDT. The PDT-treated area was examined both grossly and histologically in surgical resection specimens or patients who underwent autopsy. Tumor response was classified into four categories: complete remission (CR), significant remission (SR), partial remission (PR), and no remission (NR). CR was defined as the complete absence of tumor on endoscopy as well as on cytology and histology. SR was defined as a 60% or more reduction in tumor volume macroscopic or histologic evaluation. PR was defined as a reduction in tumor volume of 20 to 60%, and NR was defined as a reduction in tumor volume of less than 20%. The dysphagia grade as described by Krasner [9] (Table 1) was evaluated both pre- and post-treatment. All the results shown in tables are the results obtained solely with PDT.


Subsequent to initial endoscopic evaluation, six patients were categorized as having early-stage superficial (ES) type cancer. In this group, four patients were treated with either PDT alone or PDT plus conventional radiotherapy. One patient had refused surgery (case 2), 2 were inoperable due to poor pulmonary function (cases 3 and 4), and one developed superficial invasion after esophageal reconstruction (case 1). In the remaining two patients (cases 5 and 6), surgical resection was performed after PDT since residual tumor was suspected because of the rather widespread distribution of the superficial lesions in these patients. Resected specimens in these cases revealed the presence of multiple lesions, three in case 5 and two in case 6. Serial sections of these specimens, however, revealed no histological evidence of tumor at sites treated with PDT. One patient (case 5) died shortly after surgery from aspiration pneumonia, and the other (case 6) is apparently disease-free 36 months after PDT. CR was obtained in four of the six cases. The survival rate in this group averages 27 months after PDT and the five patients remain alive to date (Table 2). In the 14 patients classified as advanced invasive (AI), 9 were treated with either PDT alone or PDT plus conventional radiotherapy because of inoperability. Five others

Table 2. Patient data and therapeutic results of photodynamic therapy (PDT) in early stage superficial esophageal cancer. CR, Complete remission; SR, significant remission Case


Site (cm) from teeth

Type of tumor

Light dose (J/cm 2)

Other treatment


Current status





360 x 2





2 5 - 28







2 6 - 30











2 4 - 30



Postradiation Postradiation Surgery




25 --31





47 months alive 42 months alive 25 months alive 13 months alive Operation; death 36 months alive


152 Table 3. Patient data and therapeutic results of PDT in advanced invasive esophageal cancer. PR, Partial remission Case


Site (cm) from teeth

Type of tumor

Light d o s e (J/cm2)

Radiation therapy



Current Status

1 2 3 4 5 6 7 8 9 10 11 12 13 14

50/M 53/M 67/M 84/M 77/M 55/M 72/F 63/M 78/M 63/M 78/F 69/M 65/M 80/M

20-30 23-26 28 - 33 25-27 32-34 27 -31 32- 36 20-25 33 - 37 31 - 36 25 - 29 25-28 24-27 28-38

Depressed Depressed Stenotic Elevated Elevated Stenotic Stenotic Stenotic Stenotic Elevated Stenotic Stenotic Stenotic Stenotic

40 60+360a 50+ 180" 154 72 120 15 20 66 150 100 90 100 300

Pre Pre Pre Post Post Post Pre Pre Post Pre -

+ + + + + -


Operation; dead Operation; dead 4 months; dead 18 months; dead 13 months; alive 15 months; alive 4 months; dead 4 months; dead 8 months; dead 15 months; alive 12 months; dead 6 months; dead 8 months; alive 9 months; alive

Intratumoral PDT

were treated with surgery following PDT. Significant or partial remissions were obtained in all cases although there were no CRs in this group. The dysphagia grade improved from a mean of 4.0 to 2.8. Twelve patients were included in the assessment of survival as 2 patients died after operation. The survival rate in this group averages 9.7 months after PDT with 5 patients alive to date (Table 3).

Discussion The mechanisms by which PDT exerts its cytotoxic effects have been postulated [15]. Singlet oxygen is known to play an important role in inducing lethal cellular damage. Previous studies have shown that HpD is absorbed into the cytoplasm and tends to accumulate in mitochondria, where the first cellular changes take place [1, 7]. Cytocidal effects are thought to result from biochemical lesions causing severe disturbances in the tricarboxylic acid cycle. The preferential retention of HpD by malignant tissue makes it possible to selectively induce tumor-specific cytocidal effects, with less damage to surrounding normal tissue. In this study a low-power argon-dye laser system was used. It was observed in our patients that normal tissue which surrounded cancerous lesions was almost completely unaffected by PDT. This method of employing low-power laser light sources is fundamentally different from high-energy laser techniques such as Nd: Y A G laser which vaporizes tissue. In this paper we evaluated the effectiveness of PDT in the treatment of both ES and AI types of esophageal cancer. Fortunately, in Japan, patients with esophageal cancer are generally diagnosed and treated at the early stage of the disease owing to aggressive screening measures. Presently, the type of patient chosen for PDT has an early-stage lesion but is unsuitable for operation because of poor general health or poor cardiopulmonary function. To obtain CR in 67% of these patients with ES is very encouraging. CR was not obtained in all ES cases primarily due to technical problems such as failure to recognize the entire extent of cancerous lesions on endoscopy, and in-

sufficient photoirradiation due to tangential submucosal invasion by tumor. Improvements in the laser system, quartz fibers, and endoscopic equipment are necessary in such cases. Also, the development of more efficient photosensitizers should be beneficial. For PDT to be successful in early-stage esophageal cancer with the available technology, the lesion should be visible on endoscopy and the peripheral margins should be well delineated. Tumor invasion should be limited to within 1 cm of the luminal surface since this is the limit of tissue penetration by 630 nm wavelength light. The anatomy of the esophagus offers several advantages when compared to other organs in which luminal cancers have been treated with endoscopic PDT. Unlike the lung with its numerous branch points which make maneuvering the endoscopic equipment difficult, and the stomach with multiple rugae and pits, the esophagus is ideal, as it is straight with a relatively smooth mucosal surface. However, in patients with early-stage lung cancers readily accessible to the bronchoscope, PDT has also proved beneficial. Three patients treated at the Tokyo Medical College with earlystage lung cancers have survived for 5 years, including one who is the longest known survivor after treatment by PDT alone [8]. PDT may also be the best option in the treatment of flat recurrent foci of esophageal cancer in patients previously treated by other modalities. In this study, one patient (case 1) developed a superficially invading tumor in the cervical esophagus after esophageal reconstruction. Tumor cells persisted on biopsy after external-beam radiotherapy and he was referred to our hospital for PDT. Following endoscopic PDT, there was no gross or histologic evidence of residual tumor. The patient remains disease-free 47 months after PDT. Almost all clinical trials of PDT arid esophageal cancer have involved patients with advanced disease [2, 11]. As a measure of palliation in patients with advanced invasive disease, the dysphagia grade is a reliable measure of the quality of life after treatment, as it takes into account important factors such as the ability to swallow and increased dietary intake. We obtained an improvement in the dyspha-

153 gia grade of patients with AI disease from a mean of 4.0 to 2.8 with a mean survival of 9.7 months. McCaughan et al. evaluated quality of life in a group of patients by utilizing the Karnofsky Performance Status (KPS) and esophageal grade. A significant benefit was noted for their patients with advanced disease treated with palliative endoscopic PDT. They also reviewed the complications of conventional treatment for esophageal cancer and noted disadvantages such as the long hospital stay following surgery in such patients and the high mortality and morbidity. Endoscopic PDT offers several advantages over conventional treatment for esophageal cancer, such as low mortality, little or no interference when combined with other therapies, no limitation on performing repeat endoscopic phototherapy, together with the minimal complications and significant improvement in the quality of life of patients treated by this method [12]. Five patients underwent surgical resection after PDT in the AI group. PDT can be employed in such cases to reduce the tumor burden and extent of resection necessary or to render previously inoperable cases operable. Kato et al. described the important role of PDT in accomplishing these objectives when combined with surgery and other modalities in patients with advanced lung cancer [6]. Complications experienced by our patients after PDT were minimal and included increased skin photosensitivity (14 patients), luminal edema with a decrease in luminal diameter (8 patients) and stricture formation (2 patients), which responded well to dilation. Endoscopic reevaluation was performed 2 or 3 days after PDT and tumors were found to be soft and easily dilated, as reported by others [11]. Occasionally, edema interferes with swallowing until endoscopic reevaluation and dilation is performed. Photosensitive patients were required to avoid sunlight for at least 3 weeks following therapy. In conclusion, we have defined the indications for endoscopic PDT in esophageal cancer. They include patients with early superficial disease or patients without lymph node involvement who are unfit for surgery, where complete remission may be achieved after PDT, and patients with advanced invasive disease where PDT used as palliation can restore luminal patency and alleviate dysphagia.

References 1. Berns MW, Dahlman A, Johnson FM, Burns R, Sperling D, Guiltinan M, Siemens A, Walter R, Wright W, Wilson MH, Wile A (1982) In vitro cellular effects of hematoporphyrin derivative. Cancer Res 42:2325-2329 2. Forbes IJ, Cowled PA, Leong AS, Ward AD, Black RB, Blake AJ, Jacka FJ (1980) Phototherapyof human tumorsusinghematoporphyrin derivative. Med J Aust 2:489-493 3. DoughertyTJ (1986) Photosensitizationof malignant tumors. Semin Surg Oncol 2:24-37 4. DoughertyTJ, LawrenceG, KaufmanJH, BoyleDG, Weishaupt KR, Goldfarb A (1979) Photoradiationin the treatment of recurrent breast carcinoma. J Natl CancerInst 62: 23l -237 5. Hayata Y, Kato H, Conaka C, Ono J, Takizawa N (1982) Hematoporphyrin derivative and laser photoradiationin the treatment of lung cancer. Chest 81:269-277 6. Kato H, Konaka C, Ono J, Kawate N, Nishimiya K, Shinihara H, Saito M, Sakai H, Kito T, AizawaK, Hayata Y (1985) Preoperative laser photodynamic therapy in combination with operation in lung cancer. J Thorac Cardiovasc Surg 90:420-429 7. Kato H, Aizawa K, ShinoharaH, Konaka C, Hayata Y (1986) Cytomorphological changes caused by hematoporphyrin derivative and photodynamictherapy. Laser Life Sci 1:13-27 8. Kato H, Konaka C, Kawate N, Shinohara H, Kinoshita K, Noguchi M, OotomoS, Hayata Y (1986) Five-yeardisease-free survival of a lung cancerpatient treated only by photodynamictherapy. Chest 90: 768 770 9. Krasner N, Barr H, Skidmore C, Morris AI (1987) Palliative laser therapy for malignant dysphagia. Gut 28:792-798 10. Lipson RL, Baldes EJ, Olsen AM (1961) The use of hematoporphyrin in tumor detection. J Natl Cancer Inst 26:1-8 11. McCaughanJS, Williams TE, Bethel BH (1985) Palliation of esophageal malignancywith photodynamictherapy. Ann Thorac Surg 40: 113-120 12. McCanghanJS, Nims TA, Guy JT, Hicks WJ, Wilhams TE, Laufman LR (1989) Photodynamictherapy for esosphagealtumors. Arch Surg 124:74-80 13. Postlethwait RW (1983) Complications and deaths after operations for esophageal carcinoma. J Thorac Cardiovasc Surg 85: 827-831 14. Raab O (1900) Uber die Wirkung fluorescierender Stoffe auf Infusorien. Z Bio139:524-546 15. Weishaupt KR, Gomer CJ, Dougherty TJ (1976) Identification of singlet oxygen as the cytotoxic agent in photoinactivation of a murine tumor. CancerRes 36:2326-2329

Photodynamic therapy of esophageal carcinoma.

Photodynamic therapy (PDT) utilizing either hematoporphyrin derivative or Photofrin II is proving to be an effective modality in the treatment of earl...
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